RO4987655

RO4987655 is an orally active and highly selective MEK inhibitor with an IC₅₀ of 5.2 nM for inhibition of MEK1/MEK2. IC50 & Target: IC50: 5.2 nM (MEK1/MEK2)^[1] In Vitro: RO4987655 potently inhibits mitogen-activated protein kinase signaling pathway activation and tumor cell growth, with an in vitro IC₅₀ of 5.2 nM for inhibition of MEK1/2^[1]. RO4987655 inhibits proliferation of NCI-H2122 cells in a dose-dependent manner with an IC₅₀ value of 0.0065 μM. RO4987655 at doses ranging from 0.1 to 1.0 μM suppresses pERK1/2 already at 2 h after the start of treatment^[2]. In Vivo: Single-agent oral administration of RO4987655 (CH4987655) results in complete tumor regressions in xenograft models. RO4987655 is rapidly absorbed with a t_max of ~1 h. Exposures are dose proportional from 0.5 to 4 mg. The disposition is biphasic with a terminal t_1/2 of ~25 hr. Intersubject variability is low, 9% to 23% for C_max and 14% to 25% for area-under-the-curve (AUC). pERK inhibition is exposure dependent and is greater than 80% inhibition at higher doses. The pharmacokinetic-pharmacodynamic relationship is characterized by an inhibitory E_max model (E_max ~100%; IC₅₀ 40.6 ng/mL) using nonlinear mixed-effect modeling^[1]. Female athymic nude mice are randomized into study groups. The tumors size is estimated with digital caliper and PET scans performed on days 0, 1, and 3 with 1.0, 2.5, and 5.0 mg/kg RO4987655. The vehicle treatment does not inhibit the NCI-H2122 tumor xenograft growth over this time frame. In contrast, RO4987655 treatment results in 119% tumor growth inhibition (TGI) at 1.0 mg/kg, 145% TGI at 2.5 mg/kg and 150% TGI at 5.0 mg/kg on day 3. PET imaging shows that [¹⁸F] FDG uptake in the xenografts decreases within 24 h (day 1) from the administration of RO4987655^[2].